We propose to study the rates of biosynthesis and turnover of the poly-gamma-glutamyl metabolites of methotrexate. These studies would be carried out first in normal rats, then in mice infected with L-1210 leukemia (methotrexate sensitive) and finally in S180 mice (methotrexate resistant). Information obtained in the above studies will be translated and used as a guide in the chemical synthesis of new poly- gamma-glutamyl analogs of methotrexate. These new drugs will be tested for their chemotherapeutic effectiveness in the L1210 and S180 cancer systems.